U.S. patent number 4,230,705 [Application Number 05/725,597] was granted by the patent office on 1980-10-28 for 6-phenyl-1,2,4-triazolo[4,3-b]pyridazines and their uses in treating anxiety.
This patent grant is currently assigned to American Cyanamid Company. Invention is credited to Jay D. Albright, George R. Allen, Jr., John W. Hanifin, Jr., Daniel B. Moran.
United States Patent |
4,230,705 |
Allen, Jr. , et al. |
October 28, 1980 |
6-Phenyl-1,2,4-triazolo[4,3-b]pyridazines and their uses in
treating anxiety
Abstract
This disclosure describes novel substituted
6-phenyl-1,2,4-triazolo[4,3-b]pyridazines useful as anxiolytic
agents.
Inventors: |
Allen, Jr.; George R. (Old
Tappan, NJ), Hanifin, Jr.; John W. (Suffern, NY), Moran;
Daniel B. (Suffern, NY), Albright; Jay D. (Nanuet,
NY) |
Assignee: |
American Cyanamid Company
(Stamford, CT)
|
Family
ID: |
24915205 |
Appl.
No.: |
05/725,597 |
Filed: |
September 22, 1976 |
Current U.S.
Class: |
514/248; 544/236;
544/224; 544/239 |
Current CPC
Class: |
C07D
295/145 (20130101); C07D 237/20 (20130101); C07D
487/04 (20130101); C07D 237/08 (20130101); C07D
237/14 (20130101); C07D 237/12 (20130101); C07D
237/04 (20130101) |
Current International
Class: |
C07D
237/12 (20060101); C07D 237/00 (20060101); C07D
237/14 (20060101); C07D 237/08 (20060101); C07D
237/04 (20060101); C07D 237/20 (20060101); C07D
295/00 (20060101); C07D 295/145 (20060101); C07D
487/04 (20060101); C07D 487/00 (20060101); C07D
487/04 (); A61K 031/50 (); C07D 237/14 () |
Field of
Search: |
;260/25AC ;424/250
;544/236 |
Foreign Patent Documents
Other References
Deev, et al., Chem. Abs. 82, 125338r (1973). .
Yurugi et al., Chem. Abs. 80, 37073d (1973). .
Leclerc et al., Bull. Soc. Chim. France..
|
Primary Examiner: Berch; Mark L.
Attorney, Agent or Firm: Conroy, Jr.; Edward A.
Claims
We claim:
1. The method of meliorating anxiety in a mammal which comprises
administering internally to said mammal an effective amount of a
compound selected from the group consisting of those of the
formula: ##STR3## wherein R.sub.1, R.sub.2, and R.sub.3 are each
individually selected from the group consisting of hydrogen and
alkyl having up to four carbon atoms with the first proviso that
when R.sub.1 and R.sub.2 are both hydrogen then R.sub.3 may not be
methyl and with the second proviso that when R.sub.2 and R.sub.3
are both methyl then R.sub.1 may not be hydrogen; and the
pharmacologically acceptable acid-addition salts thereof.
2. A therapeutic composition in dosage unit form useful for
meliorating anxiety in mammals comprising from about 0.03 milligram
to about 10.0 milligrams per kilogram of body weight per daily
dosage unit, in association with a pharmaceutical carrier, of a
compound selected from the group consisting of those of the
formula: ##STR4## wherein R.sub.1, R.sub.2, and R.sub.3 l are each
individually selected from the group consisting of hydrogen and
alkyl having up to four carbon atoms with the first proviso that
when R.sub.1 and R.sub.2 are both hydrogen then R.sub.3 may not be
methyl and with the second proviso that when R.sub.2 and R.sub.3
are both methyl then R.sub.1 may not be hydrogen; and the
pharmacologically acceptable acid-addition salts thereof.
Description
BRIEF SUMMARY OF THE INVENTION
This invention relates to new organic compounds and, more
particularly, is concerned with novel substituted
6-phenyl-1,2,4-triazolo[4,3-b]pyridazines which may be represented
by the following structural formula: ##STR1## wherein R.sub.1,
R.sub.2, and R.sub.3 are each individually selected from the group
consisting of hydrogen and alkyl having up to four carbon atoms
with the first proviso that when R.sub.1 and R.sub.2 are both
hydrogen then R.sub.3 may not be methyl and with the second proviso
that when R.sub.2 and R.sub.3 are both methyl then R.sub.1 may not
be hydrogen. The invention also includes novel compositions of
matter containing the above-defined compounds useful as anxiolytic
agents and the method of meliorating anxiety in mammals
therewith.
DETAILED DESCRIPTION OF THE INVENTION
The novel compounds of the present invention are generally
obtainable as white to pale yellow crystalline materials having
characteristic melting points and absorption spectra and which may
be purified by recrystallization from common organic solvents such
as methanol, ethanol, dimethylformamide, acetone, chloroform, ethyl
acetate, and the like. They are appreciably soluble in non-polar
organic solvents such as toluene, carbon tetrachloride, and the
like but are relatively insoluble in water. The organic bases of
this invention form non-toxic acid-addition salts with a variety of
pharmacologically acceptable organic and inorganic salt-forming
reagents. Thus, acid-addition salts, formed by admixture of the
organic free base with one or two equivalents of an acid, suitably
in a neutral solvent, are formed with such acids as sulfuric,
phosphoric, hydrochloric, hydrobromic, sulfamic, citric, lactic,
malic, succinic, tartaric, acetic, benzoic, gluconic, ascorbic, and
the like. The acid-addition salts are relatively insoluble in
non-polar organic solvents such as diethyl ether, benzene, toluene,
and the like but are appreciably soluble in water. For purposes of
this invention, the free bases are equivalent to their non-toxic
acid-addition salts.
The novel compounds of the present invention may be readily
prepared in accordance with the following reaction scheme: ##STR2##
wherein R.sub.1, R.sub.2, and R.sub.3 are each individually
hydrogen or alkyl having up to four carbon atoms. In accordance
with the above reaction scheme, an appropriately substituted
3-benzoylpropionic acid (I) is reacted with hydrazine hydrate at
the reflux temperature in a lower alkanol solvent for a period of
12-24 hours to provide the corresponding
4,5-dihydro-6-phenyl-3(2H)-pyridazinone (II). Treatment of the
4,5-dihydro-6-phenyl-3(2H)-pyridazinone (II) with bromine in
glacial acetic acid solvent at steam bath temperature for a period
of 2-4 hours provides the corresponding 6-phenyl-3(2H)-pyridazinone
(III). Conversion of the 6-phenyl-3(2H)-pyridazinone (III) to the
corresponding 3-chloro-6-phenylpyridazine (IV) is achieved by
treatment with excess phosphorus oxychloride at steam bath
temperature for a period of 4-8 hours. Interaction of the
3-chloro-6-phenylpyridazine (IV) with an acylhydrazine (V) at the
reflux temperature in a lower alkanol solvent for a period of 24-48
hours provides the corresponding 6-phenyl-1,2,4-triazolo[
4,3-b]pyridazines (VI) of the present invention.
The novel compounds of the present invention possess central
nervous system activity at non-toxic doses and as such are useful
as anxiolytic agents. That is, they produce certain responses in
standard tests with laboratory animals which are known to correlate
well with relief of anxiety in man. The compounds have been tested
pharmacologically and found to have such properties with a
desirable wide spread between doses producing anxiolytic activity
and toxic symptoms.
The anti-anxiety properties of the novel compounds of the present
invention have been established in a test which indicates
anxiolytic activity by the measure of protection from convulsions
resulting from the administration of pentylenetetrazole. Graded
dose levels of the compounds of this invention were administered
orally, in a 2% starch vehicle, to groups of at least 5 rats. At
the estimated time of peak effect, the rats were treated
intravenously with pentylenetetrazole at a dose of 21 to 23 mg./kg.
of body weight. This dose is estimated to cause clonic seizures in
99% of unprotected rats. The effective dose (ED.sub.50) of the test
compound for protection of 50% of the animals is calculated by the
method of D. H. Finney in "Statistical Methods in Biological
Assay", Second Edition, Hafner Publishing Co., New York, 1964, pp.
456-457. Representative results are given in Table I which follows
in comparison with chlordiazepoxide or meprobamate, which were
tested in exactly the same manner. It has been reported [R. T. Hill
and D. H. Tedeschi, "Animal Testing and Screening Procedures in
Evaluating Psychotropic Drugs" in "An Introduction to
Psychopharmacology", Eds. R. R. Rech and K. E. Moore, Raven Press,
New York, pp. 237-288 (1971)] that there is a high degree of
correlation between antagonism of pentylenetetrazole seizures in
rats and anti-anxiety effects in higher warm-blooded animals.
TABLE I ______________________________________ Protection Against
Clonic Seizures Caused By Pentylenetetrazole in Rats Medium
Effective Oral Dose Compound mg./kg. ED.sub.50
______________________________________ 3-Methyl-6-phenyl-1,2,4- 3
triazolo[4,3-b]pyridazine Chlordiazepoxide 2.5 Meprobamate 22
6-Phenyl-1,2,4-triazole- 9, 5 [4,3-b]pyridazine
______________________________________
Another test which has been used to assess anti-anxiety effects is
a non-conditioned passive avoidance procedure described by J. R.
Vogel, B. Beer and D. E. Clody, "A Simple and Reliable Conflict
Procedure for Testing Anti-Anxiety Agents", Psychopharmacologia,
Vol. 21, pp. 1-7 (1971). A conflict situation is induced in rats by
a modification of this method. To groups of six naive
Sprague-Dawley rats (200-220 grams), previously deprived of water
for forty-eight hours and food for 24 hours, are administered
graded oral doses of test compound suspended in 2% starch vehicle
also containing 2 drops of polyethylene glycol and polysorbate 80,
or vehicle alone (controls). At the time of peak effect each rat is
placed in a plexiglass box fitted with a drinkometer circuit
connected between the stainless steel grid floor and a stainless
steel drinking tube inserted in a hole in one of the walls of the
box. A stimulator supplying monophasic 60 cycle square wave pulses
of 0.2 milliamperes peak intensity, a timer which allows alternate
5 second "shock free" and 5 second "shock available" periods during
a 5 minute test period, an electromagnetic counter to count the
number of shocks received by the rat during the shock available
period and a delay of one half second between the successive shocks
are incorporated into the drinkometer circuit. After the rat is
placed in the box, it is allowed to explore and drink 10% dextrose
solution supplied through the tap. After twenty seconds of
continuous unpunished drinking, the timer and drinkometer circuits
are activated and 5 second shock free and 5 second shock available
periods alternate. The number of shocks received by the rat during
a 5 minute test period is recorded. The percentage of rats that
receive 9 or more shocks in 4 to 5 minutes at each dose level is
used as positive response in calculation of the median effective
dose (ED.sub.50). The results of this test on representative
compounds of this invention appear in Table II below.
TABLE II ______________________________________ Median Effective
Dose Compound (ED.sub.50 mg./kg.)
______________________________________ 3-Methyl-6-phenyl-1,2,4- 100
triazolo[4,3-b]pyridazine Chlordiazepoxide 9.6 Meprobamate 51.9
______________________________________
The novel compounds of the present invention have been found to be
highly useful for meliorating anxiety in mammals when administered
in amounts ranging from about 0.03 milligram to about 10.0 mg. per
kilogram of body weight per day. A preferred dosage regimen for
optimum results would be from about 0.1 mg. to about 5.0 mg. per
kilogram of body weight per day, and such dosage units are employed
that a total of from about 7.0 milligram to about 0.35 gram of
active compound for a subject of about 70 kg. of body weight are
administered in a 24 hour period. This dosage regimen may be
adjusted to provide the optimum therapeutic response. For example,
several divided doses may be administered daily or the dose may be
proportionally reduced as indicated by the exigencies of the
therapeutic situation. A decided practical advantage of this
invention is that the active compounds may be administered in any
convenient manner such as by the oral, intravenous, intramuscular,
or subcutaneous routes.
Compositions according to the present invention having the desired
clarity, stability and adaptability for parenteral use are obtained
by dissolving from 0.10% to 10.0% by weight of active compound in a
vehicle consisting of a polyhydric aliphatic alcohol or mixtures
thereof. Especially satisfactory are glycerin, propylene glycol,
and polyethylene glycols. The polyethylene glycols consist of a
mixture of non-volatile, normally liquid, polyethylene glycols
which are soluble in both water and organic liquids and which have
molecular weights of from about 200 to 1500. Although the amount of
active compound dissolved in the above vehicle may vary from 0.10
to 10.0% by weight, it is preferred that the amount of active
compound employed be from about 3.0 to about 9.0% by weight.
Although various mixtures of the aforementioned non-volatile
polyethylene glycols may be employed, it is preferred to use a
mixture having an average molecular weight of from about 200 to
about 400.
In addition to the active compound, the parenteral solutions may
also contain various preservatives which may be used to prevent
bacterial and fungal contamination. The preservatives which may be
used for these purposes are, for example, myristyl-gamma-picolinium
chloride, benzalkonium chloride, phenethyl alcohol,
p-chlorophenyl-.alpha.- glycerol ether, methyl and propyl parabens,
and thimerosal. As a practical matter, it is also convenient to
employ antioxidants. Suitable antioxidants include, for example,
sodium bisulfite, sodium metabisulfite, and sodium formaldehyde
sulfoxylate. Generally, from about 0.05 to about 0.2%
concentrations of antioxidant are employed.
For intramuscular injection, the preferred concentration of active
compound is 0.25 to 0.50 mg./ml. of the finished compositions. The
novel compounds of the present invention are equally adapted to
intravenous administration when diluted with water or diluents
employed in intravenous therapy such as isotonic glucose in
appropriate quantities. For intravenous use, initial concentrations
down to about 0.05 to 0.25 mg./ml. of active ingredient are
satisfactory.
The active compounds of the present invention may be orally
administered, for example, with an inert diluent or with an
assimilable edible carrier, or they may be enclosed in hard or soft
shell gelatin capsules, or they may be compressed into tablets, or
they may be incorporated directly with the food of the diet. For
oral therapeutic administration, the active compounds may be
incorporated with excipients and used in the form of tablets,
troches, capsules, elixirs, suspensions, syrups, wafers, and the
like. Such compositions and preparations should contain at least
0.1% of active compound. The percentage of the compositions and
preparations may, of course, be varied and may conveniently be
between about 2% to about 60% of the weight of the unit. The amount
of active compound in such therapeutically useful compositions is
such that a suitable dosage will be obtained. Preferred
compositions or preparations according to the present invention are
prepared so that an oral dosage unit form contains between about
0.1 to 5.0 milligrams of active compound.
The tablets, troches, pills, capsules and the like may also contain
the following: a binder such as gum tragacanth, acacia, corn starch
or gelatin; excipients such as dicalcium phosphate; a
disintegrating agent such as corn starch, potato starch, alginic
acid and the like; a lubricant such as magnesium stearate; and a
sweetening agent such as sucrose, lactose or saccharin may be added
or a flavoring agent such as peppermint, oil of wintergreen, or
cherry flavoring. When the dosage unit form is a capsule, it may
contain, in addition to materials of the above type, a liquid
carrier such as a fatty oil. Various other materials may be present
as coatings or to otherwise modify the physical form of the dosage
unit. For instance, tablets, pills, or capsules may be coated with
shellac, sugar or both. A syrup or elixir may contain the active
compound, sucrose as a sweetening agent, methyl and propylparabens
as preservatives, a dye and flavoring such as cherry or orange
flavor. Of course, any material used in preparing any dosage unit
form should be pharmaceutically pure and substantially non-toxic in
the amounts employed.
The invention will be described in greater detail in conjunction
with the following specific examples.
EXAMPLE 1
______________________________________ Preparation of 50 mg.
Tablets Per Tablet Per 10,000 Tablets
______________________________________ 7,8-Triethyl-6-
phenyl-1,2,4-tria- 0.050 gm. zolo[4,3-b]pyridazine 500 gm. 0.080
gm. Lactose 800 gm. 0.010 gm. Corn Starch (for mix) 100 gm. 0.008
gm. Corn Starch (for paste) 75 gm. 0.148 gm. 1475 gm. 0.002 gm.
Magnesium Stearate (1%) 15 gm. 0.150 gm. 1490 gm.
______________________________________
The 3,7,8-triethyl-6-phenyl-1,2,4-triazolo[4,3-b]pyridazine,
lactose and corn starch (for mix) are blended together. The corn
starch (for paste) is suspended in 600 ml. of water and heated with
stirring to form a paste. This paste is then used to granulate the
mixed powders. Additional water is used if necessary. The wet
granules are passed through a No. 8 hand screen and dried at
120.degree. F. The dry granules are then passed through a No. 16
screen. The mixture is lubricated with 1% magnesium stearate and
compressed into tablets in a suitable tableting machine.
EXAMPLE 2
______________________________________ Preparation of Oral
Suspension Ingredient Amount ______________________________________
3,8-Di-n-butyl-6-phenyl-1,2,4- triazolo[4,3-b]pyridazine 500 mg.
Sorbitol solution (70% N.F.) 40 ml. Sodium benzoate 150 mg.
Saccharin 10 mg. Red dye 10 mg. Cherry flavor 50 mg. Distilled
water qs ad 100 ml. ______________________________________
The sorbitol solution is added to 40 ml. of distilled water and the
3,8-di-n-butyl-6-phenyl-1,2,4-triazolo[4,3-b]pyridazine is
suspended therein. The saccharin, sodium benzoate, flavor and dye
are added and dissolved. The volume is adjusted to 100 ml. with
distilled water. Each ml. of syrup contains 5 mg. of
3,8-di-n-butyl-6-phenyl-1,2,4-triazolo[4,3-b]pyridazine.
EXAMPLE 3
Preparation of Parenteral Solution
In a solution of 700 ml. of propylene glycol and 200 ml. of water
for injection is suspended 20.0 grams of
7,8-di-n-propyl-6-phenyl-1,2,4-triazolo[4,3-b]pyridazine
monohydrochloride with stirring. After suspension is complete, the
pH is adjusted to 5.5 with hydrochloric acid and the volume is made
up to 1000 ml. with water for injection. The formulation is
sterilized, filled into 5.0 ml. ampoules each containing 2.0 ml.
(representing 40 mg. of drug) and sealed under nitrogen.
EXAMPLE 4
Preparation of
3,7,8-trimethyl-6-phenyl-1,2,4-triazolo[4,3-b]pyridazine
A 200 g. portion of 3-benzoyl-2,3-dimethyl-propionic acid and 60 g.
of hydrazine hydrate are added to one liter of ethyl alcohol and
stirred at reflux for 18 hours. The reaction mixture is then cooled
in an ice bath and collected in a conventional manner to afford
4,5-dihydro-4,5-dimethyl-6-phenyl-3(2H)-pyridazinone as a cream
colored solid. This product is partially dissolved in 600 ml. of
glacial acetic acid. To this is added, portionwise, a solution of
50 ml. of bromine in 100 ml. of glacial acetic acid, while warming
on a steam bath (approximately 15% of the bromine solution is added
to the reaction mixture before warming is started and about one
hour is required to complete the addition during which time
quantities of hydrogen bromide gas are given off). After the
addition is completed, the reaction mixture is heated on the steam
bath for one hour, and then the mixture is poured onto crushed ice.
The resulting solid is vacuum filtered, washed copiously with
water, and air dried to give 4,5-dimethyl-6
-phenyl-3(2H)-pyridazinone as a cream colored solid. This material
is added to 800 ml. of phosphorus oxychloride and is heated on a
steam bath for 5 hours. The reaction mixture is concentrated to
remove the excess phosphorus oxychloride and is then diluted with
cold water. The resulting solid is vacuum filtered, washed
copiously with water, and air dried to give
3-chloro-4,5-dimethyl-6-phenylpyridazine as a pinkish solid. A 10
g. portion of this product plus 8 g. of N-acetylhydrazine and 100
ml. of n-butyl alcohol is allowed to stir at reflux for 48 hours.
The reaction mixture is cooled in an ice bath and the resulting
solid is vacuum filtered, washed first with petroleum ether and
then with water, and is air dried. The solid is recrystallized from
ethyl alcohol after treatment with activated charcoal and is dried
in vacuo to give
3,7,8-trimethyl-6-phenyl-1,2,4-triazolo[4,3-b]pyridazine as a white
solid.
EXAMPLE 5
Preparation of
7-methyl-6-phenyl-1,2,4-triazolo[4,3-b]pyridazine
A 10 g. portion of 6-(p-bromophenyl)-5-methyl-3(2H)-pyridazinone
[J. Medicinal Chem. 17, 281 (1974)] and 100 ml. of phosphorus
oxychloride are heated at steam bath temperature for 3 hours. The
mixture is added dropwise to cold water while stirring. The
resulting solid is filtered and washed with water to afford
3-(p-bromophenyl)-6-chloro-4-methyl pyridazine as a grey solid. A
mixture of 1.5 g. of this compound, 0.64 g. of formylhydrazine and
25 ml. of n-butyl alcohol is stirred at reflux for 18 hours. The
reaction mixture is cooled in an ice bath, filtered, and the solid
is recrystallized from methyl alcohol giving
6-(p-bromophenyl)-7-methyl-1,2,4-triazolo[4,3-b]pyridazine.
A mixture of 10 g. of the above material, 30 ml. of ammonium
hydroxide, 250 ml. of ethyl alcohol and a catalytic amount of 10%
palladium on charcoal is shaken in a Parr shaker for 18 hours. The
uptake of 35 pounds of hydrogen is complete in 2 hours. The
reaction mixture is then filtered to remove the catalyst and the
filtrate is concentrated to a white solid which is triturated with
petroleum ether. The solid is collected by filtration, air dried
and recrystallized from methanol-ethyl acetate to give
7-methyl-6-phenyl-1,2,4-triazolo[4,3-b]pyridazine as white
crystals, m.p. 188.degree.-190.degree. C.
EXAMPLE 6
Preparation of
3-methyl-6-phenyl-1,2,4-triazolo[4,3-b]pyridazine
The title compound is prepared by the method of Duffin et al. as
set forth in British Pat. No. 839,020 issued on June 29, 1960.
EXAMPLE 7
Preparation of 3,8
-dimethyl-6-phenyl-1,2,4-triazolo[4,3-b]pyridazine
The title compound is prepared by the method of Leclerc &
Wermuth as set forth in Bull. Soc. Chim. France, No. 5, 1752
(1971).
EXAMPLE 8
Preparation of
7-isopropyl-6-phenyl-1,2,4-triazolo[4,3-b]pyridazine
The procedure of Example 4 is repeated substituting equimolecular
amounts of 3-benzoyl-3-isopropyl-propionic acid and
N-formylhydrazine for the 3-benzoyl-2,3-dimethyl-propionic acid and
N-acetylhydrazine employed in that example. There is thus obtained
the title compound in equally good yield.
EXAMPLE 9
Preparation of
8-isobutyl-6-phenyl-1,2,4-triazolo[4,3-b]pyridazine
Following the general procedure of Example 4,
3-benzoyl-2-isobutyl-propionic acid is converted to
3-chloro-4-isobutylpyridazine which is treated with
N-formylhydrazine to give the title compound.
EXAMPLE 10
Preparation of
3-ethyl-7-methyl-6-phenyl-1,2,4-triazolo[4,3-b]pyridazine
The general procedure of Example 4 is repeated but replacing the
3-benzoyl-2,3-dimethyl-propionic acid and N-acetylhydrazine
employed in that example with 3-benzoyl-3-methyl-propionic acid and
N-propionylhydrazine.
EXAMPLE 11
Preparation of 6-phenyl-1,2,4-triazolo[4,3-b]pyridazine
A 10 g. portion of 3-chloro-6-phenylpyridazine (Chem. Abs., 44,
5616i), 6.6 g. of formylhydrazine and 100 ml. of n-butanol are
refluxed for 48 hours. The reaction mixture is cooled in an ice
bath. The resulting solid is filtered, washed with petroleum ether
and water and air dried giving
6-phenyl-1,2,4-triazolo[4,3-b]pyridazine as tan crystals, m.p.
138.degree.-139.degree. C.
EXAMPLE 12
Preparation of
8-methyl-6-phenyl-1,2,4-triazolo[4,3-b]pyridazine
A mixture of 13.2 g. of 4-methyl-6-phenyl-3(2H)-pyridazinone and
200 ml. of phosphorus oxychloride is heated on a steam bath for 18
hours. The reaction mixture is filtered. The filtrate is
concentrated free of excess phosphorus oxychloride. The residue is
stirred with ice water and filtered. The solid is washed with water
and air dried giving 3-chloro-4-methyl-6-phenylpyridazine as a
cream colored solid.
A mixture of 2.05 g. of the above product, 1.2 g. of
formylhydrazine and 50 ml. of n-butanol is stirred and refluxed for
48 hours. The reaction mixture is concentrated free of solvent and
the residue is stirred with diethyl ether. The mixture is filtered
giving a cream colored solid. This solid is recrystallized from
methanol after treatment with activated charcoal. The methanol
filtrate is allowed to evaporate slowly at room temperature
resulting in the formation of white needles along with a dark
yellow oil. The oil is removed and the needles are washed with a
small amount of diethyl ether which is decanted. The needles are
then recrystallized from methanol-diethyl ether-petroleum ether
giving 8-methyl-6-phenyl-1,2,4-triazolo[4,3-b]pyridazine as white
crystals, m.p. 150.degree.-151.degree. C.
EXAMPLE 13
Preparation of
3-n-propyl-6-phenyl-1,2,4-triazolo[4,3-b]pyridazine
A mixture of 10 g. of 3-chloro-6-phenylpyridazine, 11.2 g. of
butyric acid hydrazide and 100 ml. of n-butanol is heated at reflux
for 40 hours. The solution is cooled and the precipitate is
filtered and washed with petroleum ether and water. The filtrate is
concentrated to an oil which forms a precipitate upon the addition
of petroleum ether. The precipitate is collected and washed with
petroleum ether and water. The solids are combined and
recrystallized from 30 ml. of ethanol giving
3-n-propyl-6-phenyl-1,2,4-triazolo[4,3-b]pyridazine as crystals,
m.p. 123.degree.-125.degree. C.
EXAMPLE 14
Preparation of 3-ethyl-6-phenyl-1,2,4-triazolo[4,3-b]pyridazine
A mixture of 7.6 g. of 3-chloro-6-phenylpyridazine, 7.4 g. of
propionic acid hydrazide and 60 ml of n-butanol is stirred at
reflux temperature for 48 hours. The solution is cooled in a
chilled room, concentrated to remove the solvent and triturated
with water giving crystals. The mixture is filtered, washed with
petroleum ether and water and dried. The product is recrystallized
from 20 ml. of ethanol giving
3-ethyl-6-phenyl-1,2,4-triazolo[4,3-b]pyridazine, m.p.
133.degree.-135.degree. C.
* * * * *